Various antimicrobial agents are known for use as preservatives in ophthalmic compositions. The antimicrobial agents should have a broad spectrum of antimicrobial activity but must also be non-irritating to the eye. Some of the most common antimicrobial agents used in ophthalmic applications include benzalkonium chloride, chlorhexidine, polyquaternium-1, poly(hexamethylene biguanide) alexidine, and thimerosal.
Each antimicrobial compound has its own degree of efficacy against a specific collection of microorganisms. Because a single antimicrobial agent may not necessary be efficacious against all microorganisms of interest in a safe and effective concentration range, it is sometimes beneficial to introduce another compound into the formulation to enhance disinfection or preservative efficacy against the microorganisms. Some compounds, if added, provide an improvement in antimicrobial activity of another agent or alone have mild antimicrobial properties. U.S. Pat. No. 5,817,277 describes the use of tromethamine in combination with several antimicrobial agents or as an antimicrobial agent to disinfect contact lenses. U.S. Pat. Nos. 5,342,620; 5,505,953; and 6,503,497 describe that a complex of borate buffer and one or more polyols can improve the antimicrobial efficacy of an ophthalmic solution.
U.S. Pat. Nos. 6,319,464 and 6,949,218 describe that low molecular weight amino alcohols such as 2-amino-2-methyl-1-propanol (AMP), 2-dimethylamino-2-methyl-1-propanediol (DMAMP), 2-amino-2-ethyl-1,3-propanediol (AEPD), 2-amino-2-methyl-1,3-propanediol (AMPD), and 2-amino-1-butanol (AB) can enhance the activity of antimicrobial agents such as various biguanides including chlorhexidine, alexidine and poly(hexamethylene biguanide) (PHMB). PCT Publ. No. WO95/30414 discloses the use of one or more amino acids in a specified range increased the antimicrobial activity, particularly against Acanthamoeba. Compositions are disclosed that include glycine and histidine. US Publ. Nos. US20030153622 and US20060122080 disclose the optional use of neutral amino acids, including glycine, in combination with an amino alcohol, an acid including glycolic acid and aspartic acid.
European Patent No. 0923950 discloses the combination of polyquaternium-1, an amino acid and a non-ionic tonicity adjusting agent. A specific example of histidine in combination with a phosphate buffer was disclosed. U.S. Pat. No. 5,494,937 discloses the combination of a borate buffer, an amino acid (e.g., alanine, glycine and histidine) and a polyol.
There continues to be a need for ophthalmic compositions with improved disinfecting systems that are simple to use, are effective against a broad spectrum of microorganisms, are non-toxic and do not cause ocular irritation. There is also a need for ophthalmic compositions that maintain some buffering capacity such as contact lens packaging solutions and preservative-free solutions.